SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming
- PMID: 36580912
- PMCID: PMC9715480
- DOI: 10.1016/j.cell.2022.11.030
SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming
Abstract
How SARS-CoV-2 penetrates the airway barrier of mucus and periciliary mucins to infect nasal epithelium remains unclear. Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Phosphoproteomics and kinase inhibition reveal that microvillar remodeling is regulated by p21-activated kinases (PAK). Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.
Keywords: COVID-19; SARS-CoV-2; airway epithelial cells; cilia; microvilli; organoids; protein kinases; proteomics; respiratory synctital virus; respiratory virus.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests The authors declare no competing interests.
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Comment in
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Across the mucus.Nat Rev Microbiol. 2023 Feb;21(2):65. doi: 10.1038/s41579-022-00842-6. Nat Rev Microbiol. 2023. PMID: 36513767 Free PMC article.
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Motile cilia and microvillar: accomplices of SARS-CoV-2 in penetrating mucus barrier and infecting airway epithelium.Signal Transduct Target Ther. 2023 Mar 14;8(1):117. doi: 10.1038/s41392-023-01387-7. Signal Transduct Target Ther. 2023. PMID: 36918546 Free PMC article. No abstract available.
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